Gemcitabine-cisplatin doublet is a standard first-line regimen for metastatic gallbladder cancer (GBC), though prospective real-world data remains scarce. We evaluated the efficacy, safety, and prognostic factors in the North Indian patients. Between March 2021 and December 2022, all patients with histologically proven metastatic GBC were prospectively enrolled. Eligible patients had ECOG 1-2 and adequate organ function. Gemcitabine 1000mg/m² (days 1, 8) and cisplatin 75mg/m² (days 1-2) were given every 3 weeks for up to 6 cycles, until progression or intolerance. Patients receiving ≥ 2 cycles were evaluable for efficacy. Responses were assessed by RECIST 1.1. Kaplan-Meier, univariate, and multivariate analyses were performed. Sixty-three patients were included in the study(Mean Age 56 years; 62% female). ORR was 63.5%; DCR 84.5%. Median PFS was 5.0 months; median OS 11.0 months. Six-month OS was 82.1%, 12-month OS 36.9%. Independent predictors of PFS included % change in CA19-9, platelet-lymphocyte ratio, alkaline phosphatase, and extra-abdominal disease. Neutropenia (any grade 73%, grade 3-4: 27%) was the most common toxicity; G-CSF was used therapeutically in 41%. Non-hematological AEs were mild-to-moderate. No treatment-related deaths occurred. Gemcitabine-cisplatin remains effective and tolerable in metastatic GBC. Despite the emergence of Gemcitabine-Cisplatin with durvalumab as new standard, this prospective dataset provides valuable real-world outcomes from a high-incidence region with limited access to immunotherapy.

Age-standardized mortality-to-incidence ratio for gallbladder cancer in the world.

Development of a novel predictive nomogram to prevent 'futile surgery' in gallbladder cancers: A single center analysis of 1196 resected gallbladder cancers.

Aloperine exerts anti-tumor effect and activates the tumor cell-intrinsic STING pathway in gallbladder cancer.

Therapeutic potential of IFIT2 in human diseases.

T3 gallbladder cancer: surgical outcomes according to the mode of tumor spread and treatment considerations for oncological resectability.

The largest multi-institutional cohort analysis of bile spillage in incidental gallbladder cancer was presented by van Dooren et al The study offers important insights, though certain methodological limitations and interpretative challenges temper the strength of its conclusions. We address these, clarify how statistical findings intersect with clinical relevance for bile spillage, propose a refined classification system, and provide global epidemiological context.

Resected intrahepatic cholangiocarcinoma: Is adjuvant chemotherapy associated with improved overall survival?

Objective: To investigate the pathological characteristics of post-cholecystectomy specimens from patients with benign gallbladder diseases. Methods: This retrospective case series study analyzed clinical and pathological data from 1 712 patients who underwent cholecystectomy for benign gallbladder diseases at the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine between September 2022 and August 2024. The cohort included 757 males and 955 females, with an age (M(IQR)) of 57(23) years (range: 14 to 91 years). Clinical and pathological features were analyzed. The χ² test was used to compare clinical characteristics between patients with neoplastic and non-neoplastic polyps. Factors statistically significant in the χ² test were subsequently included in a binary logistic regression analysis. Results: Postoperative pathological examination revealed gallbladder cancer in 7 patients (0.41%). These 7 cases, including 2 with pT3 stage cancer, were not detected preoperatively by various imaging examinations (ultrasound+magnetic resonance cholangiopancreatography/MRI plain scan in 3 cases, ultrasound+enhanced MRI in 1 case, ultrasound+enhanced CT in 2 cases, enhanced CT+enhanced MRI in 1 case). Gallbladder adenoma was found in 23 cases (1.34%), neoplastic polyps (including cholesterol polyps with dysplasia) in 29 cases (1.69%), and non-neoplastic polyps in 154 cases (9.00%). Statistically significant differences were observed in age and polyp number between patients with neoplastic and non-neoplastic polyps (χ²=10.436 and 8.030; both P<0.05). Binary logistic regression analysis identified age ≥60 years (P=0.003) and solitary polyps (P=0.009) as risk factors for neoplastic polyps. Mucosal dysplasia was present in 164 cases (9.58%), including 9 cases of severe dysplasia, 4 of which exhibited focal carcinomatous transformation. Gallbladder polyps combined with stones were found in 90 cases (5.26%), among which 10 were associated with adenoma and mucosal dysplasia, and 2 showed focal carcinomatous transformation. Conclusions: The incidence of incidental gallbladder carcinoma was 0.41%. Intraoperative bile spillage can severely compromise prognosis. Preoperative imaging demonstrates a low detection rate for neoplastic polyps. Particular vigilance for neoplastic polyps is warranted in patients aged ≥60 years or with solitary polyps. Cholecystectomy should be performed promptly for benign gallbladder diseases meeting surgical indications.

Accurate assessment of tumor invasion depth is essential for determining the surgical strategy for gallbladder cancer; however, preoperative assessment remains challenging. This study assessed the utility of intraoperative narrow-band imaging (NBI) of the gallbladder serosal surface for estimating tumor invasion depth. Thirty-nine patients with suspected gallbladder cancer underwent intraoperative observation of the gallbladder serosa using NBI. The NBI findings were classified based on vascular irregularities and correlated with postoperative histopathological data. Among the 39 patients, 26 (66.7%) were diagnosed with gallbladder cancer. All patients with positive NBI (n = 14) were pathologically confirmed to have gallbladder cancer. Positive NBI was significantly associated with ≥ T2 invasion and increased microvasculature in the subserosal layer (p < 0.001), as well as with lymphatic invasion (p < 0.001). Diagnostic sensitivities for ≥ T2 invasion were 79.5% for intraoperative NBI, 69.4% for plane CT, and 63.0% for EUS. Intraoperative NBI may be useful for evaluating tumor depth and lymphatic involvement in patients suspected to have gallbladder cancer, which can support intraoperative surgical decision-making.

Biliary tract cancers (BTCs), which include intrahepatic and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are aggressive malignancies with a poor prognosis. Standard therapies such as surgical resection and chemotherapy offer limited survival benefits, particularly in advanced stages. Immunotherapy has recently emerged as a promising new treatment approach in the management of BTCs. This review provides a detailed analysis of the immunobiology of BTCs, highlighting the evidence supporting the use of ICIs either alone or in combination with chemotherapy. It also discusses emerging immunotherapeutic strategies, response biomarkers, ongoing clinical trials, and potential future directions.

To systematically review the latest evidence on risk factors and surgical treatment for gallbladder cancer (GBC), with a focus on current controversies and consensus in international guidelines, analyze the application prospects of minimally invasive surgery in advanced GBC, and provide direction for clinical practice and future research. Literature on GBC risk factors, molecular mechanisms, and treatment strategies published from 2018 to 2024 was retrieved from databases including PubMed, Web of Science, and CNKI. The retrieved literature was summarized, compared, and critically analyzed. The pathogenesis of GBC involves a combination of genetic, environmental, and metabolic factors. Beyond gallstones and polyps, mutations in TP53 and ERBB2/ERBB3 genes, metabolic syndrome (obesity, hyperglycemia, hyperlipidemia), and chronic infections (Salmonella, Helicobacter) are significant risk factors. Surgical resection remains the primary curative approach, yet the optimal extent of surgery is debated: Is hepatic resection always necessary for T1b stage? What is the oncological safety of laparoscopic surgery for T2 stage? What is the value of extended resection for T4 stage? Recently, targeted therapies (e.g., against ERBB2, NTRK) and mmune checkpoint inhibitors (anti-PD-1/PD-L1)have shown promise in advanced GBC. Combating GBC requires a comprehensive strategy encompassing health education, screening of high-risk populations, precise staging, and individualized multimodal treatment. Future research should focus on building molecular subtype-based prognostic models, conducting high-level clinical studies to resolve surgical controversies, and exploring the integration of novel adjuvant therapies with traditional surgery.

To evaluate the safety and efficacy of neoadjuvant gemcitabine, cisplatin, and S-1 (GCS) chemotherapy for resectable biliary tract cancer (BTC) and FDG-PET-positive lymph nodes in a multicenter phase II study (KHBO1201). Patients with resectable BTC (intrahepatic/extrahepatic bile duct, gallbladder, or ampullary cancers) and FDG-PET-positive lymph nodes received GCS chemotherapy: gemcitabine/cisplatin on Day 1 and oral S-1 for 7 days, repeated every 2 weeks for 3-6 cycles. Surgery was planned 4-8 weeks later if the tumor was deemed resectable. The primary endpoint was the curative resection rate. Secondary endpoints were the completion rate, radiological response, radiological/pathological complete response (CR) of FDG-PET-positive lymph nodes, and 1-year survival (UMIN000009831). Twenty-five patients were enrolled. Twenty-three (92%) completed GCS without treatment-related deaths; grade 3 biliary infection occurred in 8.0%. Curative resection was achieved in 60% with a morbidity rate of 40%. The radiological response rate was 13%, and the radiological and pathological CR rates of FDG-PET-positive lymph nodes were 24% and 28%, respectively. The 1-year survival rate was 75%. Neoadjuvant GCS chemotherapy is safe, feasible, and potentially effective for resectable BTC with FDG-PET-positive lymph nodes. A randomized phase III trial (JCOG1920) is underway to compare neoadjuvant GCS chemotherapy with upfront surgery (jRCTs031200388).

Gallbladder cancer (GBC), an aggressive malignancy of the biliary tract, is characterized by pronounced geographical variation and a poor prognosis, with a five-year survival rate below 20%. Despite its low global incidence, it ranks as the fifth most prevalent gastrointestinal cancer. The aim of this review is to provide a comprehensive understanding of the molecular mechanisms underpinning GBC progression, with a particular focus on the pivotal role of transcription factors (TFs) in its pathogenesis. This review delineates how aberrant regulation of TFs contributes to tumor initiation, progression, and therapeutic resistance, and to discuss the translational potential of targeting these factors for clinical benefit. Tumor suppressor TFs such as p53 and p16 frequently undergo genetic alterations, including mutations, deletions, or epigenetic silencing, leading to impaired cell cycle control, DNA repair, and apoptosis. Conversely, oncogenic TFs including TCF4, MYBL2, NF-kB, AP-1, Snail, c-MYC, SP1, FOXK1, KLF-5, STAT3 and BIRC7 are often upregulated in GBC, promoting unchecked proliferation, epithelial–mesenchymal transition (EMT), metastasis, and therapeutic resistance. This review aims to bridge current molecular insights with emerging therapeutic approaches, with particular emphasis on innovative interventions such as proteolysis-targeting chimeras (PROTACs), RNA-based therapeutics, CRISPR-driven genome editing, and epigenetic modulators, which collectively represent promising strategies for achieving more effective and personalized treatment outcomes in patients with GBC.

Gallbladder cancer has a poor prognosis due to its aggressive nature and late detection. Adenosquamous subtypes are rare and poorly characterized at the molecular level. Patient-derived xenograft (PDX) models preserve tumor heterogeneity and support evolutionary studies. Longitudinal specimens-primary, metastatic, and PDX-from the same patient, combined with immunohistochemistry (IHC), allow investigation of tumor progression and cellular origin. A 65-year-old woman with gallbladder cancer underwent cholecystectomy, followed by omental metastasectomy upon relapse. A single-cell suspension from the metastatic lesion was injected into NOD-SCID mice to generate a PDX model. IHC assessed marker expression in primary, metastatic, and PDX tumors. A targeted next-generation sequencing somatic panel analyzed clonal evolution. P63 confirmed the adenosquamous subtype. The PDX model retained histopathological and marker features of the primary and metastatic tumors. Diagnostic (CK7, CK17, Muc1, Muc5AC) and prognostic markers (EpCAM, CRP, S100P, AQP1, Podoplanin) were preserved across all tumors. Genomic analysis identified KRAS (G12V)mutation as the main oncogenic driver and LRP1B (Q48R) mutationas a putative tumor suppressor retained in all tumors. The secondary tumor acquired PIK3CA (E65D) and LRP1B (G37437) mutations. The PDX gained mutations in chromatin remodeling genes ARID2, ARID1A, and BAP1. Clonal trajectory analysis identified four subclones, indicating branched and linear evolution patterns. We successfully established a PDX model of gallbladder adenosquamous carcinoma, with KRAS (G12V) identified as a potential initiating mutation, and the probable tumor-initiating cell is derived from an EpCAM-positive putative cancer stem cell. Sequential analysis revealed the emergence of resistant clones and adaptive selection of chromatin remodelers in the PDX model.

Rationale:Porcelain gallbladder (PG) is an academic term to define a special as well as rare condition of some gallbladder diseases. So far, some issues still remain a discussion, such as etiopathogenesis, clinical features, correlation with gallbladder cancer, and surgical indication. We described a typical PG case, and reviewed some English literature as well as relevant cases from our institutions, aiming to further illustrate some issues mentioned above.Patient concerns:Herein, we describe a 54-year-old obesity woman with hypertension and prediabetes who presented with recurrent abdominal pain and indigestion for 35 years, with diagnosis of chronic cholelithiasis.Diagnoses:She insisted on nonsurgical management for many years until a ring, high-dense shadow classically associated with PG, was found on computed tomography scan in the latest visit of the Emergency Department.Interventions:Therefore, she underwent a laparoscopic cholecystectomy.Outcomes:The patient recovered uneventfluly after surgery, and the post oprative pathology confirmed a PG without any cancer cells under microscopy. After a month of follow-up, she was very satisfied with the clinical outcomes, with no surgery-related complications.Lessons:PG has a potential though low risk of gallbladder cancerization. If patients’ condition permit, minimally invasive cholecystectomy is still a prioritized choice due to its safety and reliability as well.

Neoadjuvant treatment has demonstrated clinical benefits in advanced gallbladder cancer (GBC). However, the overall response rate remains suboptimal, and the underlying mechanisms driving treatment efficacy are not fully understood. This study aimed to evaluate the therapeutic effects of neoadjuvant chemo-immunotherapy (NAT) combining gemcitabine, nab-paclitaxel, and anti-PD-1 immunotherapy in advanced GBC, and to investigate the associated tumor microenvironment (TME) alterations. Single-cell RNA sequencing and multiplex immunohistochemistry were utilized to analyze the cellular composition of the TME in patients who successfully underwent downstaging. NAT significantly reshaped the tumor-immune landscape, characterized by an expansion of follicular helper T (Tfh) cells and the formation of tertiary lymphoid structures (TLSs) in 50% of treated tumors. Inflammatory cancer-associated fibroblasts (CAFs) increased and exhibited upregulation of CCL19 and CXCL12, potentially promoting Tfh cell recruitment and TLS formation. Additionally, NAT led to an expansion of GZMB+ cytotoxic CD8+ T cells with an exhausted phenotype in GBC, but not in adjacent normal tissues. The treatment also increased the number and effector functions of natural killer cells while reducing tumor-promoting macrophages and angiogenesis-related CAFs. Furthermore, NAT decreased the cancer stem cell-like subpopulation while increasing a cancer cell subset with enhanced antigen-presenting capacity. This study suggested the potential efficacy of NAT in advanced GBC and revealed alterations in the TME following treatment. The findings provided insights into the mechanisms underlying NAT responses and offered valuable directions for optimizing therapeutic strategies in GBC.

Biliary tract cancer (BTC) comprises a group of heterogenous malignancies that arise from the bile ducts (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma) and the gallbladder (gallbladder cancer). Collectively, these malignancies carry a poor prognosis, which is attributed to the advanced stage at presentation. Historically, advanced BTC had a reputation of being less responsive to chemotherapy, a theory that was changed in the last decade, likely due to improved biliary drainage techniques that consequently improve liver function. Few advances have been made in the treatment of advanced and unresectable BTC in the past couple of years.

Background: Gall bladder cancer (GBC) is an aggressive disease often presenting at an advanced stage. It is the most common hepatobiliary malignancy in eastern India. Extended cholecystectomy (EC), the currently accepted definitive surgery for GBC, being a major surgical procedure, has considerable morbidity and mortality. Aims and Objectives: This study aims to study the profile of patients undergoing EC and evaluate the peri-operative events and post-operative outcome. Materials and Methods: It was conducted over 1.5 years. 30 patients undergoing EC for radiologically-suspicious/peri-operative findings suggestive of GBC were considered as per the inclusion and exclusion criteria. Results: Of the 30 patients studied, 24 (80%) were &gt;50 years age, 20 (66.7%) were female, 27 (90%) were non-vegetarian, 26 (86.7%) had pain abdomen, and 7 (23.3%) had pallor. No patient had a lump abdomen, jaundice, icterus, or clinically detectable lymphadenopathy. On ultrasonography (USG), 22 (73.3%) had intraluminal mass, 25 (83.3%) had gallstones; on computed tomography scan, 24 (80%) had intraluminal mass, 17 (56.7%) had no adjacent structure invasion, and 11 (36.7%) had liver bed invasion. None required resection of the extrahepatic biliary tree. Post-operatively, 7 (23.3%) required intensive care, 1 (3.3%) had a hematoma, 6 (20%) had surgical site infection, and 4 (13.3%) had bile leak. Histopathology showed adenocarcinoma gall bladder in 25 (83.3%) and papillary carcinoma in 1 (3.3%). Post-surgery USG at 1 month was normal in 25 (83.3%) patients, and 4 (13.7%) had mild collection in the Hepatorenal Pouch of Morrison. All had a normal USG report at 3 months post-surgery. Conclusion: GBC is more common in females aged 51–60 years. Pain abdomen is the most common symptom. Post-operative intensive care is not required for majority of the patients undergoing EC. Most complications can be managed conservatively.

Adequate lymphadenectomy and adjuvant capecitabine warrant survival benefit in gallbladder cancer.